2. Academic Validation
  3. Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia

Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia

  • Sci Rep. 2015 Nov 24;5:17154. doi: 10.1038/srep17154.
Beryl Royer-Bertrand 1 2,  Silvia Castillo-Taucher 3,  Rodrigo Moreno-Salinas 4,  Tae-Joon Cho 5,  Jong-Hee Chae 6,  Murim Choi 7,  Ok-Hwa Kim 8,  Esra Dikoglu 2,  Belinda Campos-Xavier 2,  Enrico Girardi 9,  Giulio Superti-Furga 9,  Luisa Bonafé 2,  Carlo Rivolta 1,  Sheila Unger 10,  Andrea Superti-Furga 2 11
Affiliations

Affiliations

  • 1 Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
  • 2 Centre for Molecular Diseases, Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
  • 3 Sección Genética, Hospital Clínico Universidad de Chile, and Sección Citogenética, Laboratorio, Clínica Alemana de Santiago, Santiago, Chile.
  • 4 Unidad de Genética, Hospital Regional Rancagua, Rancagua, Chile; and ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
  • 5 Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Republic of Korea.
  • 6 Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea.
  • 7 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 8 Department of Radiology, Woorisoa Children's Hospital, Saemalro, Guro-gu, Seoul 08291, Republic of Korea.
  • 9 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • 10 Medical Genetics Service, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.
  • 11 Department of Pediatrics and Pediatric Surgery, University of Lausanne and Lausanne University Hospital (CHUV), Lausanne, Switzerland.
PMID: 26598328 DOI: 10.1038/srep17154
Abstract

We and Others have reported mutations in LONP1, a gene coding for a mitochondrial chaperone and protease, as the cause of the human CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373). Here, we delineate a similar but distinct condition that shares the epiphyseal, vertebral and ocular changes of CODAS but also included severe microtia, nasal hypoplasia, and other malformations, and for which we propose the name of EVEN-PLUS syndrome for epiphyseal, vertebral, ear, nose, plus associated findings. In three individuals from two families, no mutation in LONP1 was found; instead, we found biallelic mutations in HSPA9, the gene that codes for mHSP70/mortalin, another highly conserved mitochondrial chaperone protein essential in mitochondrial protein import, folding, and degradation. The functional relationship between LONP1 and HSPA9 in mitochondrial protein chaperoning and the overlapping phenotypes of CODAS and EVEN-PLUS delineate a family of "mitochondrial chaperonopathies" and point to an unexplored role of mitochondrial chaperones in human embryonic morphogenesis.

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